title: Long-term antidepressant treatment inhibits neuropathic pain-induced CREB and PLCγ-1 phosphorylation in the mouse spinal cord dorsal horn.
abstract: The effect of long-term administration of imipramine, a tricyclic antidepressant, on the phosphorylation status of cyclic adenosine monophosphate-responsive element-binding protein (CREB), mitogen-activated protein kinase family members, and phospholipase γ-1 (PLCγ-1) was investigated in the dorsal horn of the spinal cord following peripheral nerve lesion. Nerve injury induced an ipsilateral long-lasting increased phosphorylation of CREB and PLCγ-1 but not extracellular signal-regulated kinase (ERK1,2), p38, and c-Jun N-terminal kinase. Daily administration of imipramine (5, 10, or 30 mg/kg) for 21 days progressively reduced both tactile-induced neuropathic pain hypersensitivity and thermal hyperalgesia. After withdrawal of treatment, the antinociceptive effect of imipramine was gradually abolished but still remained for at least 3 weeks. Conversely, no analgesic effect was observed with short-term imipramine treatment. Moreover, imipramine therapy reversed nerve injury-induced CREB and PLCγ-1 phosphorylation but had no effect on ERK1,2, p38, and c-Jun N-terminal kinase activity. These results indicate that long-term administration of imipramine may prevent some of the harmful changes in the spinal cord dorsal horn following nerve injury. However, imipramine analgesic effect takes time to develop and mature, which might explain in part why the clinical analgesic effect of tricyclic antidepressants develops with a delay after the beginning of treatment. Our data also provide evidence that prolonged imipramine treatment may induce antinociception in neuropathic pain conditions because of its action on the PLCγ-1/CREB-signaling pathway.
  
  
  CONCLUSIONS
  This article demonstrates that long-term treatment with imipramine reverses some of the marked effects induced by peripheral nerve injury in the spinal dorsal horn that contribute to long-term maintenance of sensory disorder, providing a new view to the mechanisms of action of these drugs.
authors.affiliation: Pain Neurobiology Laboratory, Department of Physiology, Ribeirão Preto School of Medicine, University of São Paulo, São Paulo, Brazil.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Kusuda
authors.forename: Maria I
authors.initials: MI
authors.lastname: Ravanelli
authors.forename: Flaviane
authors.initials: F
authors.lastname: Cadetti
authors.forename: Adriano
authors.initials: A
authors.lastname: Franciosi
authors.forename: Karina
authors.initials: K
authors.lastname: Previdelli
authors.forename: Sonia
authors.initials: S
authors.lastname: Zanon
authors.forename: Guilherme
authors.initials: G
authors.lastname: Lucas
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000627:therapeutic use*; D000929:Antidepressive Agents, Tricyclic / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects; D015153:Blotting, Western; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D007099:Imipramine / Q000627:therapeutic use; D007150:Immunohistochemistry; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009437:Neuralgia / Q000188:drug therapy* / Q000378:metabolism*; D010147:Pain Measurement / Q000187:drug effects; D051966:Phospholipase C gamma / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D020671:Posterior Horn Cells / Q000378:metabolism*; D012585:Sciatica / Q000188:drug therapy / Q000473:pathology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000928:Antidepressive Agents; D000929:Antidepressive Agents, Tricyclic; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D051966:Phospholipase C gamma; D007099:Imipramine
keywords: Cyclic adenosine monophosphate–responsive element-binding protein; antidepressant; imipramine; neuropathic pain; phospholipase γ-1; spinal cord